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The field of cardiovascular regenerative therapy has rapidly moved from the laboratory to the clinic. Several phase I and II clinical trials have been conducted using adult stem cell therapy (1,2), and the field is now entering an important stage with the announcement of the first pivotal phase III trial powered to achieve a mortality endpoint in patients with acute ST-segment elevation myocardial infarction by a European consortium (BAMI [The Effect of Intracoronary Reinfusion of Bone Marrow Derived Mononuclear Cells (BM-MNC) on All-Cause Mortality in Acute Myocardial Infarction] trial). Although the original hope for adult stem cell therapy was the regeneration of lost cardiac myocytes (3), there is little evidence to date that adult stem cells lead to significant regeneration of cardiac myocytes when delivered in the setting of acute myocardial infarction (AMI) or ischemic cardiomyopathy. That said, adult stem cell therapy has consistently shown clinical benefit in AMI and chronic heart failure (4), and its investigation at the bench and in the clinic continues at a rapid pace.

Several years ago we proposed that cardiovascular regenerative medicine will develop over 3 stages (5). Stage I was the cell stage in which specific populations or mixed populations of adult stem cells would be delivered to patients with AMI or chronic heart failure. Stage II would focus on the delivery of the paracrine factors that are released by and the effectors of adult stem cells. This stage would focus on gene transfer, cell-based gene transfer protein therapy, or small molecule delivery. Stage III would achieve true myocardial regeneration in which embryonic stem cells or induced pluripotent stem cells (iPSCs) would be used to introduce new cardiac myocytes to the injured myocardium. Importantly, this stage will require tissue engineering to learn how to generate and introduce ex vivo–generated contractile units to the injured myocardium.

Stages I and II are under investigation in both the basic and clinical laboratories. Our group has been privileged in leading the pre-clinical and clinical development of the multipotent adult progenitor cell for the prevention of cardiac dysfunction in AMI (6) (Clinicaltrials.gov; NCT00677222). We have similarly pioneered the science and clinical translation of the stromal cell–derived factor 1 for the prevention and treatment of cardiac dysfunction (7,8) (Clinicaltrials.gov; NCT01082094). Dozens of other groups throughout the world have similarly studied and translated adult stem cells for the prevention and treatment of cardiac dysfunction (9,10).

In this issue of the Journal, Dai et al. (11) demonstrate the complexity of stage III of cardiac regenerative medicine—true myocardial regeneration. In their study, they developed a patch that they term Tri-P for tricell patch because it contains cardiac myocytes derived from iPSCs, endothelial cells, and mouse embryonic fibroblasts. The authors elegantly demonstrated the need for each of the cell types and that the combination of just endothelial cells and iPSC-derived cardiac myocytes did not result in a homogeneous patch. These findings demonstrate that the inclusion of critical cell types without an organizing or supportive cell type that releases critical paracrine factors will be insufficient for patch generation and further confirm observations from multiple research groups that stromal cells (e.g., fibroblasts) are critical for organized neovascularization (12). Their studies also demonstrate that the draping of the patch over the injured myocardium 7 days after myocardial infarction led to significant improvements in cardiac function and remodeling 4 weeks later (11).

Although these findings are of interest and important, the authors went on to investigate how myocardial fibrosis affects the engraftment of and functional response to the patch. Ultimately one of the significant challenges of true myocardial regeneration is how best to introduce the cardiogenic patch or contractile unit to the injured myocardium, particularly because cell orientation and cell-cell junctions in the Tri-P are initially random and obtaining an aligned patch of cells suitable for transplantation is challenging (13). In this study, the authors compared the effects of the Tri-P in wild-type mice and AC6 transgenic mice. The AC6 (adenylyl cyclase 6) transgenic develop less fibrosis and, in particular, less type I collagen than wild-type mice. The authors convincingly demonstrate across a number of parameters that the decrease in fibrosis correlates with improved engraftment of the Tri-P, and functional response with increased vascular density and improved remodeling and function of the myocardium.

Other studies have demonstrated an important inverse relationship between myocardial fibrosis and stem cell–based repair of the heart. Xiang et al. (14,15) demonstrated that inhibition of myocardial fibrosis through down-regulation of plasminogen activator inhibitor 1 activity led to greater stem cell recruitment to the heart, improved vascular density, and myocardial function. Of course there are limits because the complete inhibition of plasminogen activator inhibitor 1 uniformly leads to myocardial rupture (16).

Based on this study, one can speculate that the fibrosis that is present in the chronically remodeled myocardium of patients with chronic heart failure and ischemic cardiomyopathy could limit the efficacy of the contractile units in myocardial patches. If future studies validate this speculation, then the field will need to develop novel delivery strategies for the integration of myocardial patches. The recent negative results of the efficacy of scar resection in the STITCH (Simplified Treatment Intervention to Control Hypertension) trial (17) may need to be revisited if we find that stem cell–generated myocardial patches need to bridge viable border zones. Conversely, one can envision a role for biologics that can modify the fibrotic area to enhance engraftment and growth of the myocardial patch. Regardless of the approach, it seems likely that true myocardial regeneration with ex vivo–generated myocardial patches will be the purview of the cardiothoracic surgeon in the foreseeable future.

Footnotes

Dr. Penn is funded by the Skirball Foundation and UO1-HL087314. Dr. von Recum has reported that he has no relationships relevant to the contents of this paper to disclose.

↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

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